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Infection and Immunity, October 2007, p. 4792-4798, Vol. 75, No. 10
0019-9567/07/$08.00+0     doi:10.1128/IAI.00587-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Depletion of Alveolar Macrophages Decreases the Dissemination of a Glucosylceramide-Deficient Mutant of Cryptococcus neoformans in Immunodeficient Mice ^,

Departments of Biochemistry and Molecular Biology,¹ Microbiology and Immunology,² Division of Infectious Diseases, Medical University of South Carolina, Charleston, South Carolina 29425³

Received 23 April 2007/ Returned for modification 26 May 2007/ Accepted 19 July 2007

In previous studies we showed that a Cryptococcus neoformans mutant lacking glucosylceramide (gcs1) is avirulent and unable to reach the brain when it is administered intranasally into an immunocompetent mouse and is contained in a lung granuloma. To determine whether granuloma formation is key for containment of C. neoformans gcs1, we studied the role of C. neoformans glucosylceramide in a T- and NK-cell-immunodeficient mouse model (Tg26) in which alveolar macrophages (AMs) are not activated and granuloma formation is not expected. The results show that Tg26 mice infected with gcs1 do not produce a lung granuloma and that the gcs1 mutant proliferates in the lungs and does disseminate to the brain, although its virulence phenotype is dramatically reduced. Since gcs1 can grow only in acidic niches, such as the phagolysosome of AMs, and not in neutral or alkaline environments, such as the extracellular spaces, we hypothesize that in immunodeficient mice gcs1 proliferates inside AMs. Indeed, we found that depletion of AMs significantly improved Tg26 mouse survival and decreased the dissemination of gcs1 cells to the central nervous system. Thus, these results suggest that the growth of gcs1 in immunodeficient mice is maintained within AMs. This study highlights the hypothesis that AMs may exacerbate C. neoformans infection in conditions in which there is severe host immunodeficiency.

Published ahead of print on 30 July 2007.

Supplemental material for this article may be found at http://iai.asm.org/.

Editor: A. Casadevall

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